Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19

Key Points Question Is the use of anakinra plus the standard of care effective compared with the standard of care alone in reducing the probability of requiring mechanical ventilation among patients with severe COVID-19 pneumonia? Findings In this randomized clinical trial with 179 patients, the proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (77.1% for anakinra group vs 85.9% for standard of care group). Meaning This study did not find evidence of effectiveness of anakinra vs the standard of care in reducing the need for mechanical ventilation among patients with severe COVID-19 pneumonia, and future research should assess anakinra in patients with less-severe pneumonia.

m2) or receive continuous renal replacement therapy, hemodialysis or peritoneal dialysis. Uncontrolled hypertension (sitting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg). Administration of plasma from convalescent patients who have recovered from SARS-CoV-2 infection.
History of hypersensitivity or allergy to any component of the study drug.
Enrollment in another concurrent intervention clinical trial, or intake of an investigational medication within three months or 5 half-lives prior to inclusion in this study, if deemed to interfere with the objectives of this study as assessed by the investigator. Predictable inability to cooperate with given instructions or study procedures.

Procedures
Anakinra Dose selection: Anakinra was given intravenously 100 mg four times (every 6 hours) a day (total daily dose 400 mg) for a maximum of 15 days if needed according to clinical response. The dose was chosen based on the range of doses used in clinical trials of anakinra in critically ill patients. More precisely, anakinra is approved for the chronic treatment of a number of inflammatory diseases as a subcutaneous treatment (at doses of 100 mg/day or in weight-based doses of up to 8 mg/kg/day). The i.v. administration of anakinra has been studied in clinical trials in healthy volunteers and in critically ill patients with sepsis and hyper-inflammation at variable i.v. doses up to 3500 mg/day over 72 hours: e.g., 2 mg/kg/hour, 20 mg/kg/day (<40 kg) and 916 mg/day (> 40kg), bolus of 100 mg followed by infusion of 2 mg/kg/hour. No safety concerns emerged in these studies. [1,5] A study in children with systemic onset juvenile arthritis complicated by refractory macrophage activation syndrome was currently ongoing at study design protocol (NCT02780583) in which anakinra was administered at dose of 10 mg/kg/day to a maximum of dose of 200 mg/day divided every 12 hours (for children ≤40 kg) or 5 mg/kg/day up to a maximum dose of 400 mg/day divided every 6 hours (children > 40 kg and adults). Based on the above, in this study anakinra was administered at a total dose of 400 mg per day, divided in 4 i.v. doses of 100 mg every 6 hours.
Standard of care-doses: The standard of care included hydroxychloroquine (400 mg two times daily, every 12 hours for 5 days) and/or lopinavir-ritonavir (800/200 mg two times daily, every 12 hours for 5-7 days) and/or azithromycin (500 mg once daily for 5 days). Background treatment with intravenous methylprednisolone pulse therapy (250-500 mg daily) administered for three consecutive days at any time during the study was recommended based on its use with anakinra in secondary hemophagocytic lymphohistiocytosis and MAS.
Concomitant therapy: The concomitant use of other IL-1 inhibitors, IL-6 inhibitors, TNF inhibitors and JAK inhibitors was not allowed. Antimicrobial therapy and prophylaxis are not limited. Permitted concomitant medications included analgesics, antibiotics, antifungals and antiviral drugs. In case of disease worsening in terms of worsening of respiratory status, the patients could be withdrawn from the study and receive rescue medication if deemed necessary by the attending physician.
Rescue Medication: All patients must have access to rescue treatment with independent of the assigned arm. If a patient withdraws due to worsening of disease, patient should be treated as a non-responder. In the case of a patient starts to worsening independent of the assigned arm, the patient will be able to receive treatments that are protocolized at their hospital. The patient could be treated with pulses of steroids, intravenous inmunoglobulins, betainterferon , immunosuppressants agents such as cyclosporin, tacrolimus and other biologic agents such as baricitinib, tocilizumab, sarilumab and ruxolitinib. If the patient need therapy with biological drugs, they should be removed from the study.

Trial conduct:
Clinical data were recorded using an eCRF. To ensure data quality, remote data monitoring was performed by dedicated trial staff who were independent of the site investigators. The trial was monitored by a contract research organization (Dynamic Science, Evidenze Clinical Research).
Imaging findings, including chest X-ray and computed tomography were interpreted by radiologists from each participant site that were entirely independent and unaware whether the patients were included in a clinical trial.